The updated international guidelines of antiretroviral therapy pose lopinavir/ritonavir (L)- or efavirenz (E)-based HAART as the first-line choice in naïve patients. Aim of our study is to review retrospectively the efficacy and tolerability of L- vs. E-based HAART in 67 naïve patients who started HAART since 2002; 36 consecutive patients treated with L plus two nucleoside analogues (NA) were compared with 31 consecutive patients who received E and two NA. At baseline, the two study groups were matched as to demographic and epidemiological features, as well as mean viral load (4.5 ± 1.3 vs. 4.3 ± 1.7 Log 10 HIV-RNA copies per millilitre, for L and E). However, the L group included a greater number of patients with prior-concurrent AIDS (P < 0.03), and showed a lower mean CD4+ count at baseline (P < 0.004). The number of early (first month) interruptions due to poor tolerability proved similar: five cases in the L group vs. four among E-treated patients, although untoward events involved the gastrointestinal tract and the CNS, respectively, for L and E. During the subsequent follow-up (921 months), laboratory examinations were performed at least quarterly, and showed a comparable virological response (as to mode of decay, and time and rate of viral suppression), in the presence of only one case of virological failure in the E group. Conversely, a more rapid immune recovery occurred in L-treated patients, regardless of the more compromised mean initial CD4+ count of this last patients group. Mid-term toxicity was significantly different, with L-treated patients who experienced an altered serum lipid profile in over 40% of cases vs. <10% recognised in the E group. The overall need of change of antiretroviral regimen due to toxicity, poor adherence, patient's request, or failure, was comparable in the two examined patient groups. When considering our experience on 67 antiretroviral-naïve patients treated with either L- or E-based HAART, more potent and rapid immunological effects were achieved in the L group, which started from a deeper immunodeficiency, while E-treated patients experienced more rare adverse events and had less compliance problems with pill burden and subjective tolerability. Virological efficacy did not prove remarkably different between L- and E-treated patients. Pending the approval of other agents useful for first-line HIV infection therapy, the selection of L- vs. E-based regimens has to take into account of the initial immunological and disease status, while more data are needed on long-term outcome, role of emerging resistance and toxicity, as well as targeted pharmacoeconomic evaluation.